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The Bit1 cell death pathway as a novel regulator of EGFR-TKI-induced apoptosis and resistance

Award Number: R16CA315530
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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The Bit1 cell death pathway as a novel regulator of EGFR-TKI-induced apoptosis and resistance - Principal Investigator/Program Director (Last, first, middle): Biliran Jr., Hector The Bit1 cell death pathway as a novel regulator of EGFR-TKI-induced apoptosis and resistance in NSCLC Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) are the gold standard for treating EGFR mutant in non-small-cell lung cancer (NSCLC) tumors. While these drugs offer significantly improved outcomes compared to traditional chemotherapy, EGFR-TKI therapy including the latest third-generation agents invariably leads to the emergence of acquired resistance due to tumor evasion of EGFR-TKI-induced apoptosis. A comprehensive understanding of the cell death mechanisms governed or influenced by EGFR-TKIs is currently lacking. The mitochondrial Bcl2 transcription of inhibitor 1 (Bit1) protein is part of an integrin regulated cell death pathway that upon its release to the cytosol triggers caspase-independent apoptosis. This lab’s prior R-15 and R16 work has provided evidence that Bit1 exerts cell death function in NSCLC via caspase-independent inhibition of the anti-apoptotic TLE1 nuclear function. Our preliminary data indicates that EGFR-TKI triggers Bit1 cytosolic release independent from mitochondrial outer membrane permeabilization (MOMP), and Bit1 ablation attenuates EGFR-TKI-induced apoptosis. Bit1 activation in TKI-resistant NSCLC triggers apoptosis primarily through caspase-independent TLE1 suppression, with new evidence indicating secondary mitochondrial engagement. In EGFR-TKI-induced drug tolerant persister cells (DTPs) which give rise to drug-resistant cells, the TLE1 transcriptional program is activated to promote survival and block Bit1 apoptosis. Based on these compelling findings, our central hypothesis is that the Bit1 cell death pathway enhances EGFR-TKI sensitivity by disrupting the TLE1-mediated pro-survival program in the nucleus and secondarily engaging mitochondrial apoptotic factors, and Bit1 activation can enhance therapeutic efficacy and overcome resistance to EGFR-TKIs. To test this hypothesis, we will address the following specific aims: 1) Elucidate the mechanisms by which the MOMP- independent Bit1 cell death pathway enhances EGFR-TKI sensitivity by disrupting the TLE1 survival transcriptional program; 2) Define the mechanisms by which the Bit1 pathway overcomes EGFR-TKI tolerance and resistance, and identify novel therapeutic targets; and 3) Determine the in vivo efficacy of Bit1 pathway activation in overcoming EGFR-TKI resistance and minimal residual disease (MRD) in EGFR-mutant NSCLC. These proposed studies, while serving as a platform to engage undergraduate students in innovative research, will offer new therapeutic opportunities to enhance EGFR-TKI efficacy and block the emergence of EGFR-TKI resistance in EGFR mutant NSCLC.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $150,000 )
2026	2026	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Cancer Biology Research	000	1	8/20/2026	NEW	$150,000
														Subtotal = $150,000

Grand Total All Awards = $150,000

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The Bit1 cell death pathway as a novel regulator of EGFR-TKI-induced apoptosis and resistance

Award Number: R16CA315530

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/20/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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